Takuya Hiraide1, Kazuo Kubota2, Yu Kono3, Seiji Watanabe4, Tomoko Matsubayashi4, Mitsuko Nakashima5, Tadashi Kaname6, Toshiyuki Fukao2, Nobuyuki Shimozawa7, Tsutomu Ogata8, Hirotomo Saitsu9. 1. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan; Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan. 2. Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan; Division of Clinical Genetics, Gifu University Hospital, Japan. 3. Department of Neurology, Fuji City General Hospital, Shizuoka, Japan. 4. Department of Pediatric Neurology, Shizuoka Children's Hospital, Shizuoka, Japan. 5. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. 6. Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan. 7. Division of Clinical Genetics, Gifu University Hospital, Japan; Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan. 8. Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan. 9. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: hsaitsu@hama-med.ac.jp.
Abstract
BACKGROUND: Biallelic variants in POLR3A encoding the largest subunit of RNA polymerase III cause POLR3-related (or 4H) leukodystrophy characterized by neurologic dysfunction, abnormal dentition, endocrine abnormalities and ocular abnormality. Recently, whole-exome sequencing enabled the discovery of POLR3A variants in cases lacking diffuse hypomyelination, the principal MRI phenotype of POLR3-related leukodystrophy. Homozygous c.1771-6C > G variants in POLR3A were recently suggested to cause striatal and red nucleus involvement without white matter involvement. CASE REPORT: Here, we report three cases in two families with biallelic POLR3A variants. We identified two sets of compound heterozygous variants in POLR3A, c.1771-6C > G and c.791C > T, p.(Pro264Leu) for family 1 and c.1771-6C > G and c.2671C > T, p.(Arg891*) for family 2. Both families had the c.1771-6C > G variant, which led to aberrant mRNA splicing. Neuropsychiatric regression and severe intellectual disability were identified in three patients. Two cases showed dystonia and oligodontia. Notably, characteristic bilateral symmetric atrophy and abnormal signal of the striatum without diffuse white matter signal change were observed in brain MRI of all three individuals. CONCLUSIONS: Striatum abnormalities may be another distinctive MRI finding associated with POLR3A variants, especially in cases including c.1771-6C > G variants and our cases can expand the phenotypic spectrum of POLR3A-related disorders.
BACKGROUND: Biallelic variants in POLR3A encoding the largest subunit of RNA polymerase III cause POLR3-related (or 4H) leukodystrophy characterized by neurologic dysfunction, abnormal dentition, endocrine abnormalities and ocular abnormality. Recently, whole-exome sequencing enabled the discovery of POLR3A variants in cases lacking diffuse hypomyelination, the principal MRI phenotype of POLR3-related leukodystrophy. Homozygous c.1771-6C > G variants in POLR3A were recently suggested to cause striatal and red nucleus involvement without white matter involvement. CASE REPORT: Here, we report three cases in two families with biallelic POLR3A variants. We identified two sets of compound heterozygous variants in POLR3A, c.1771-6C > G and c.791C > T, p.(Pro264Leu) for family 1 and c.1771-6C > G and c.2671C > T, p.(Arg891*) for family 2. Both families had the c.1771-6C > G variant, which led to aberrant mRNA splicing. Neuropsychiatric regression and severe intellectual disability were identified in three patients. Two cases showed dystonia and oligodontia. Notably, characteristic bilateral symmetric atrophy and abnormal signal of the striatum without diffuse white matter signal change were observed in brain MRI of all three individuals. CONCLUSIONS:Striatum abnormalities may be another distinctive MRI finding associated with POLR3A variants, especially in cases including c.1771-6C > G variants and our cases can expand the phenotypic spectrum of POLR3A-related disorders.
Authors: Stefanie Perrier; Laurence Gauquelin; Catherine Fallet-Bianco; Megan K Dishop; Mackenzie A Michell-Robinson; Luan T Tran; Kether Guerrero; Lama Darbelli; Myriam Srour; Kevin Petrecca; Deborah L Renaud; Michael Saito; Seth Cohen; Steffen Leiz; Bader Alhaddad; Tobias B Haack; Ingrid Tejera-Martin; Fernando I Monton; Norberto Rodriguez-Espinosa; Daniela Pohl; Savithri Nageswaran; Annette Grefe; Emma Glamuzina; Geneviève Bernard Journal: Neurol Genet Date: 2020-05-11